The present invention relates generally to devices, systems and methods for reducing concentration of a chemical entity (for example, carbon dioxide) in fluids and, particularly, to devices, systems and methods for reducing concentration of a chemical entity (for example, carbon dioxide) in fluids such as blood in which an immobilized enzyme (for example, carbonic anhydrase) is used to facilitate diffusion toward a surface or membrane.
The following information is provided to assist the reader to understand the invention disclosed below and the environment in which it will typically be used. The terms used herein are not intended to be limited to any particular narrow interpretation unless clearly stated otherwise in this document. References set forth herein may facilitate understanding of the present invention or the background of the present invention. The disclosure of all references cited herein are incorporated by reference.
Artificial lungs are employed to oxygenate the blood and to remove CO2. Hollow fiber membrane (HFM) based artificial lungs began to replace bubble oxygenators in the 1980s. In that regard, HFM-based artificial lungs exhibit improved gas exchange performance as compared to bubble oxygenators. See Iwahashi H, Yuri K, Nose Y. 2004. Development of the oxygenator: past, present, and future. J Artif Organs 7:111-120. Nose developed the first HFM type artificial lung in 1971. However, the performance of early oxygenators was unacceptable as a result of fiber wetting and plasma leak problems. Nose Y, Malchesky P S. 1981; 3-14. Therapeutic membrane plasmapheresis. In: Therapeutic plasmapheresis. Oda T (ed) Stuttgart: F. K. Schattauer Subsequently, Kamo et al. developed commercially available composite fibers which were constructed with a true membrane layer between microporous walls. Kamo J, Uchida M, Hirai T, Yasuda H, Kanada K, Takemura T. 1990. A new multilayered composite hollow fiber membrane for artificial lung. Artificial Organs 14:369-372. Although, the composite fiber had excellent plasma wetting resistance, the permeance of the membrane was insufficient for intravenous oxygenation. Recent advances in membrane technology, however, have enabled the development of noble membranes such as polyolefin-based hollow fiber membrane that exhibit both good gas permeance and high plasma wetting resistance.
Currently available artificial lungs devices typically include bundles of microporous hollow fiber membranes through which oxygen passes while blood is perfused around the fibers. A review of artificial lungs and hollow fiber membrane technology is provided in Federspiel W J, Henchir K A. 2004. Lung, Artificial: Basic principles and current applications. Encyclo Biomat Biomed Eng 910-921, the disclosure of which is incorporated herein by reference. In general, oxygen is transferred from the lumen of the fibers into the blood; while CO2 is transferred from the blood into the lumen of the fibers and is removed from the device. In the current artificial lung model, which is based on passive diffusion, the efficiency of CO2 and O2 gas exchange are limited by the fiber surface area to blood volume ratio. Gas exchange can be improved by increasing this ratio at the cost of increasing the overall size of the artificial lung device. Additionally, CO2 removal rates are limited at lower blood flow rates.
Carbon dioxide is present in blood in three primary forms: CO2 (dissolved), bicarbonate (HCO3−), or carbamate. As known in the chemical arts, CO2 is interconvertible among these forms and the various forms can be in equilibrium with each other as described by a CO2 dissociation curve. Most of the CO2 in blood, however, exists in the form of HCO3− in plasma and in red blood cells. Colton C K. 1976. Fundamentals of gas transport in blood. In: Zapol W M and Qvist J, editor. Artificial lungs for acute respiratory failure. Washington D.C.: Hemisphere Publishing Corporation. p 3-43. In that regard, approximately 94% of plasma CO2 and 82% of red blood cell CO2 is in the form of HCO3−. The two species are interconvertible via the reaction:CO2+H2OH++HCO3−
The CO2 generates via metabolic pathways in tissue and diffuses into red blood cells (RBCs), where it is hydrated into HCO3− and hydrogen ions (H+) by intracellular carbonic anhydrase (CA). The hydrogen ions formed are bound to hemoglobin while HCO3− is diffused into plasma. Jensen F B. 2004. Red blood cell pH, the Bohr effect, and other oxygenation linked phenomena in blood O2 and CO2 transport. Acta Physiol Scand 182:215-227. However, very little CO2 is hydrated in plasma because of a lack of CA in plasma. In lungs, the reaction is reversed. HCO3− is converted into CO2 via CA in red blood cells, and then exhaled. Some CA exists in lung tissue.
CA (EC 4.2.1.1; MW 30,000 Da) is a metalloenzyme with a single zinc atom, which can effectively catalyze the reversible hydration and dehydration reaction of CO2 (CO2+H2O⇄H++HCO3−). Cleland J L, Wang D I C. 1990. Refolding and aggregation of bovine carbonic anhydrase B: Quasi-elastic light scattering analysis. Biochemistry 29:11072-11078; and Stemler. 1993. An assay for carbonic anhydrase activity and reactions that produce radiolabeled gases or small uncharged molecules. Anal Biochem 210:328-331. The enzyme enhances both hydration and dehydration rates over 105-fold compared to reaction rates in the absence of CA, even though it is variable and depends on isoforms. Lindskog and Coleman, 1973 The catalytic mechanism of carbonic anhydrase. Proc Natl Acad Sci USA 70:2505-2508; Smith R G. 1988. Inorganic carbon transport in biological systems. Comp Biochem Physiol B 90:639-654. Once again, CA is usually found within RBCs and lung tissue (alveolar epithelium).
CA has been used for CO2 processing in a number of devices. For example, U.S. Pat. No. 6,946,288 discloses the use of CA to reduce CO2 levels in air. In addition, U.S. Pat. No. 6,524,843 discloses a CA immobilized bioreactor for the generation of CO2. See also, U.S. Pat. No. 6,143,556 and Published PCT International Patent Application Nos. WO 2006/089413 and WO 2004-056455.
Moreover, a few studies have demonstrated that CA can improve CO2 removal in an oxygenator. Salley et al. evaluated CO2 removal efficiency using an encapsulated CA in cellulose nitrate. Salley S O, Song J Y, Whittlesey G C, Klein M D. 1990 Immobilized carbonic anhydrase in a membrane lung for enhanced CO2 removal. ASAIO Trans 36:M486-490. Salley et al immobilized CA containing microcapsules onto flat sheet type silicone rubber membrane. They obtained about 60% enhanced CO2 removal rate (2.58 ml/min for untreated membrane and 4.15 mL/min for CA immobilized membrane). However, encapsulation resulted in an apparent 80% loss of CA activity, which likely negates the improvement in CO2 exchange and enhanced storage stability of the encapsulated enzyme as was reported in Salley S O, Song J Y, Whittlesey G C, Klein M D. Thermal, operational, and storage stability of immobilized carbonic anhydrase in membrane lungs. ASAIO J 1 992; 38(3):M684-7. Mancini et al. performed CO2 removal by employing extracorporeal CO2 removal circuits which included a bubble oxygenator, a hollow fiber oxygenator to remove CO2, and a dialyzer. Mancini II P, Whittlesey G C, Song J Y, Salley S O, Klein M D. 1990. CO2 removal for ventilatory support: A comparison of dialysis with and without carbonic anhydrase to a hollow fiber lung. ASAIO Trans 36:M675-678. Mancini et al. compared CO2 removal performance with and without free CA in the dialyzer. The CO2 removal rates were found to be 8.76 mL/min without CA and 12.18 mL/min with CA. However, the studies failed to achieve CO2 removal performance exceeding normal oxygenator using the relatively complex CO2 removal system described therein.
Although previous studies have demonstrated the presence of CA can improve CO2 gas exchange, the systems employed are not acceptable for practical use in, for example, artificial lung and other respiratory assist devices.
It remains desirable, for example, to develop improved artificial lung devices, systems and methods. Preferably, such devices, systems and methods are relatively simple in design and relatively efficient to manufacture and to operate.